Epidermal growth factor receptor (EGFR) plays an important role in the growth of solid cancers derived from a variety of tissues, and is overexpressed in 40% to 80% of non-small-cell lung cancers examined (Salomon D S, et al., Crit. Rev. Oncol. Hematol. 1995; 19:183-232; and Mendelsohn J, et al., Oncogene 2000; 19:6550-65). Overexpression of EGFR is also associated with a poor prognosis for lung cancer patients (Selvaggi G, et al., Ann. Oncol. 2004; 15:28-32). Gefitinib (Iressa, ZD1839) is an orally administered inhibitor of EGFR tyrosine kinase, a key enzyme in the EGFR signaling pathway, which is involved in the diffusion, invasion, and survival of cancer cells (Wakeling A E, et al., Cancer Res 2002; 62:5749-54).
Gefitinib has demonstrated effective antitumor effects in clinical trials enrolling patients with progressive non-small-cell lung cancers, for whom chemotherapy using platinum formulations had not demonstrated favorable effects (Fukuoka M, et al., J. Clin. Oncol. 2003; 21:2237-46.; Kim Y H, et al., Clin. Cancer Res. 2004; 10:7311-7). Based on these findings, gefitinib has been used for the treatment of advanced non-small-cell lung cancers in several countries including Japan, Australia, and the United States.
Approximately 37,000 patients with advanced non-small-cell lung cancer have been treated with this drug in Japan since its approval (Evans T L. Oncologist 2004; 9:232-8). Although gefitinib has been effective in improving the prognosis and QOL of many of those Japanese patients, 60% of them have shown no improvement in symptoms. Not only that, but 5.4% of the patients have developed severe gefitinib-induced acute interstitial lung disease (Takano T, et al., Lung Cancer 2004; 45:93-104). Therefore, an indicator that enables physicians to select patients for whom gefitinib will be efficacious is required.
However, none of the factors examined so far, including somatic EGFR mutations, have been able to determine patient responsiveness to gefitinib administration from the viewpoint of disease control or benefit to survival. Specifically, there are currently no known indicators that enable an accurate distinction between patients with low gefitinib responsiveness and patients who are responsive to gefitinib.
There are reports that patients likely to show a partial response (PR) to gefitinib can be predicted based on the presence of EGFR mutations. However, it is not possible to show clearly that patients maintaining a stable condition could gain some survival advantage (Lynch T J, et al., N. Engl. J. Med. 2004; 350:2129-39.; Paez J G et al., Science 2004; 304:1497-500.; Pao W, et al., Proc. Natl. Acad. Sci. USA 2004; 101:13306-11.; Tokumo M, et al., Clin. Cancer Res. 2005; 11:1167-73.; Mitsudomi T, et al., J. Clin. Oncol. 2005; 23:2513-20).
Recently, twelve genes associated with sensitivity to gefitinib were identified through statistical analysis of expression information on genes that are expressed in advanced non-small-cell lung cancers. In addition, a gefitinib response scoring system has been proposed based on the expression level of genes whose expression levels vary greatly between a group of patients who partially respond to gefitinib administration (PR), and a group for whom the disease progresses (PD) (Kakiuchi S, et al., Hum. Mol. Genet. 2004; 13:3029-43.; WO 2005/49829).    Patent Document 1: WO 2005/49829    Non-Patent Document 1: Kakiuchi S, et al., Hum. Mol. Genet. 2004; 13:3029-43.